17-75843827-G-C

Variant names:

• chr17-75843827-G-C
• rs959968589
• NM_199242.3:c.118-308C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199242.3(UNC13D):​c.118-308C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,224,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: UNC13D NM_199242.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359
• Publications: 0 publications found

Genes affected

UNC13D (HGNC:23147): (unc-13 homolog D) This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]

UNC13D Gene-Disease associations (from GenCC):

• familial hemophagocytic lymphohistiocytosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• hereditary hemophagocytic lymphohistiocytosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199242.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	NM_199242.3	MANE Select	c.118-308C>G		intron	N/A	NP_954712.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC13D	ENST00000207549.9	TSL:1 MANE Select	c.118-308C>G		intron	N/A	ENSP00000207549.3
	UNC13D	ENST00000588774.2	TSL:3	n.597C>G		non_coding_transcript_exon	Exon 2 of 3
	UNC13D	ENST00000412096.6	TSL:2	c.118-308C>G		intron	N/A	ENSP00000388093.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1224488 Hom.: 0 Cov.: 32 AF XY: 0.00000339 AC XY: 2 AN XY: 590014

African (AFR) AF: 0.00 AC: 0 AN: 27138

American (AMR) AF: 0.00 AC: 0 AN: 17410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17308

East Asian (EAS) AF: 0.00 AC: 0 AN: 30318

South Asian (SAS) AF: 0.00 AC: 0 AN: 59356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3300

European-Non Finnish (NFE) AF: 0.00000201 AC: 2 AN: 994962

Other (OTH) AF: 0.00 AC: 0 AN: 50102

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.97
PhyloP100		0.36
PromoterAI		-0.91	Under-expression
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs959968589; hg19: chr17-73839908;